Lay statement: Visceral leishmaniasis (VL) is a parasitic disease that is fatal if untreated. Several hundred thousand people are affected in the Indian subcontinent. Most are poor and depend on public funds or charity for treatment. Disease control is based on early diagnosis and treatment, and control of sandflies that transmit disease. Control efforts to date have given only temporary reprieve, with periodic rebound of major epidemics. This is because there are gaps in our understanding of the dynamics of disease transmission. This study is designed to identify these factors, and to evaluate novel diagnostics and vaccine candidates that have arisen through genomic sequencing of the parasite. The study will provide new knowledge and tools to allow regional governments to achieve their aim of disease control by 2015. Project description: VL in India is patchy in distribution. The determinants of disease transmission at a village and household level are not well understood. Subclinical infection is thought to play a significant role in disease transmission, but markers of subclinical infection have yet to be validated. We don't fully understand why only a small proportion of infected subjects develop clinical disease. To gain a better understanding of disease dynamics and transmission, this study will undertake (1) an exhaustive population survey of 50,000 persons for two consecutive years using household interviews, CIS technology, remote sensing data and multi-level modelling, to identify the ecological risk markers that will permit better targeting of control interventions; (2) a nested case control study to document the modifiable risk factors (e.g. nutritional) and risk markers (clinical, genetic, immunological) for VL at household and individual level, with two annual rounds of sero-survey allowing us to document incident leishmanial infections, and a 3-year longitudinal follow-up to document development of full blown VL; (3) evaluation of existing (rK39 ELISA, Direct Agglutination Test, LST) markers of infection against standard Western blot and qualitative kDNA PCR and new Quantiferon assays for T cell responses; (4) evaluation of novel (Leishmania donovani- complex specific genes) markers using qualitative and quantitative PCR, ELISA and T-cell assays; and (5) immune profiling of novel vaccine candidate in patients and endemic controls. The results will inform policy and practice for disease control in the Indian sub-continant, and add to global understanding of VL disease.